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[Cancer Research 61, 2212-2219, March 1, 2001]
© 2001 American Association for Cancer Research

Tumor Biology

Centrosome Defects Can Account for Cellular and Genetic Changes That Characterize Prostate Cancer Progression1

German A. Pihan2, Aruna Purohit, Janice Wallace, Raji Malhotra, Lance Liotta and Stephen J. Doxsey2

Department of Pathology [G. A. P., J. W., R. M.] and Program in Molecular Medicine [A. P., S. J. D.], University of Massachusetts Medical School, Worcester, Massachusetts 01655, and Department of Pathology, National Cancer Institute, Bethesda, Maryland 20892 [L. L.]

Factors that determine the biological and clinical behavior of prostate cancer are largely unknown. Prostate tumor progression is characterized by changes in cellular architecture, glandular organization, and genomic composition. These features are reflected in the Gleason grade of the tumor and in the development of aneuploidy. Cellular architecture and genomic stability are controlled in part by centrosomes, organelles that organize microtubule arrays including mitotic spindles. Here we demonstrate that centrosomes are structurally and numerically abnormal in the majority of prostate carcinomas. Centrosome abnormalities increase with increasing Gleason grade and with increasing levels of genomic instability. Selective induction of centrosome abnormalities by elevating levels of the centrosome protein pericentrin in prostate epithelial cell lines reproduces many of the phenotypic characteristics of high-grade prostate carcinoma. Cells that transiently or permanently express pericentrin exhibit severe centrosome and spindle defects, cellular disorganization, genomic instability, and enhanced growth in soft agar. On the basis of these observations, we propose a model in which centrosome dysfunction contributes to the progressive loss of cellular and glandular architecture and increasing genomic instability that accompany prostate cancer progression, dissemination, and lethality.




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